Obesity is a major contributing factor to several diseases, including type 2 diabetes, dyslipidemias and cardiovascular disease. Obesity is caused by an excess of caloric intake compared to energy expenditure. Thus, elucidation of the mechanisms that regulate energy expenditure may lead to novel and safe approaches for treating obesity and associated diseases. The family of estrogen-related receptors (ERR?, ERR? and ERR?) regulates energy homeostasis pathways. Notably, mice lacking ERR? may lead to novel and safe approaches for treating obesity and associated diseases. are lean and resistant to diet-induced obesity. As members of the nuclear receptor family, ERRs have pockets that accommodate synthetic ligands and can thus be targeted therapeutically. In support of this notion, a ligand that inhibits ERR? has been reported to decrease adiposity and increase insulin sensitivity in mice. However, the mechanisms by which loss or inhibition of ERR? results into protection from obesity are not known. Moreover, the specific roles of the different ERRs in adipose tissue are far from understood and appear surprisingly diverse, with ERR?, ERR? and ERR? activating similarly many genes that support mitochondrial oxidative capacity, but working antagonistically at others. In the proposed work, we will elucidate the specific functions and relative contributions of ERR?, ERR? and ERR?, and of the novel ERR coregulator Gadd45? to energy homeostasis. We will use genetically modified mice and primary cultures derived from such mice to elucidate shared and unique roles of the different ERR isoforms in primary adipocytes and in adipose tissues in vivo. We will also test the extent to which the ERR coregulator Gadd45? regulates adaptive responses in brown adipose tissue. We expect our studies to elucidate how ERRs affect whole body energy balance, and establish their potential as targets for small molecules that could benefit patients with obesity and obesity related diseases. PUBLIC HEALTH RELEVANCE: Obesity and obesity-related diseases, such as Type 2 diabetes, dyslipidemia and cardiovascular disease are increasing at an alarming rate world-wide. The proposed research will elucidate mechanisms that regulate energy expenditure in the adipose tissue, and may therefore lead to safe approaches for treating obesity and obesity-related diseases.